The ability to provide therapeutic topical drugs and/or oxygen to distressed skin tissue in order to promote healing is critical for many medical skin conditions.
Most of the skin or mucosal membrane diseases or disorders are the result of inflammation caused by aging processes, metabolic disorders, surgical and post surgical procedures, environmental and lifestyle conditions, personal hygiene deficiencies, injuries, and inflammatory agents, in which systemic conditions within the body generally yield problematic skin and add to the breakdown and overacidity of the skin, such as, but not limited to, bacterial, fungal, viral, parasitic, autoimmune, allergic, hormonal and/or malignant inflammatory agents. The most common skin diseases or disorders include diabetic skin conditions, pressure ulcers caused by friction and shearing, diaper or infant rashes, incontinence dermatitis and abraded, excoriated skin, eczema, psoriasis and general dermatitis, including contact dermatitis, atopic dermatitis and seborrheic dermatitis. Other common skin injuries include flame, sun, and radiation induced burns, bites from insects and animals, sports chafing and heat rash injuries, and infections from ingrown hairs or nails in the nailbed, along with dry, cracked feet, hands and extremities due to both disease and environmental factors.
In the Textbook of Aging Skin, 2008, Miranda Farage, Kenneth W. Miller, and Howard J. Maibach, incorporated herein by reference in its entirety, it is noted: “Although the human skin is incredibly durable, like all other organ systems, it is affected by aging. A sophisticated and dynamic organ comprising 17% of the body's weight, the skin primarily acts as the barrier between the internal environment and the world outside. Yet it performs numerous functions beyond simply acting as a barrier: homeostatic regulation, prevention of percutaneous loss of fluid, electrolytes, and proteins, temperature maintenance; sensory perception; and immune surveillance.
“Distinguishing the precludable aspects of cutaneous aging (primarily hormonal and lifestyle influences) from the inexorable (primarily intrinsic aging) is essential to preventing and treating the ailments of the aging skin.”
Aging processes and inactivity, combined with diabetic conditions in long term care settings pose some of the most advanced dermatological problems, affecting the patient's health as a whole.
In the Textbook of Aging Skin, 2008, Miranda Farage, Kenneth W. Miller, and Howard J. Maibach, it is noted: “Because permeability (of the skin itself) does not appear to be significantly increased in the skin of the aged individual, it has been generally assumed that barrier function does not alter significantly with aging.” Thus, while skin itself becomes increasingly distressed and/or compromised due to the aging process, the importance of the barrier function played by skin does not change as we age.
In pressure wound staging, wounds can be classified from Stage I to IV with the addition of an unstageable wound as follows:
Stage I is the most superficial, indicated by non-blanchable redness that does not subside after pressure is relieved. This stage is visually similar to reactive hyperemia seen in skin after prolonged application of pressure. Stage I pressure ulcers can be distinguished from reactive hyperemia in two ways: a) reactive hyperemia resolves itself within ¾ of the time pressure was applied, and b) reactive hyperemia blanches when pressure is applied, whereas a Stage I pressure ulcer does not. The skin may be hotter or cooler than normal, have an odd texture, or perhaps be painful to the patient. Although easy to identify on a light-skinned patient, ulcers on darker-skinned individuals may show up as shades of purple or blue in comparison to lighter skin tones.
Stage II is damage to the epidermis extending into, but no deeper than, the dermis. In this stage, the ulcer may be referred to as a blister or abrasion.
Stage III involves the full thickness of the skin and may extend into the subcutaneous tissue layer. This layer has a relatively poor blood supply and can be difficult to heal. At this stage, there may be undermining damage that makes the wound much larger than it may seem on the surface
Stage IV is the deepest, extending into the muscle, tendon or even bone.
Unstageable pressure ulcers are covered with dead cells, or eschar and wound exudate, so the depth cannot be determined.
Research has indicated that most pressure ulcers are acidic in the most inflamed areas, and that aging skin becomes more acidic over time. According to the Archives of Dermatological Research, volume 298, number 9, 413-420, incorporated by reference herein in its entirety, wound healing is a complex regeneration process, which is characterized by intercalating degradation and reassembly of connective tissue and epidermal layer. The pH value within the wound-milieu influences indirectly and directly all biochemical reactions taking place in this process of healing. Interestingly, pH is so far a neglected parameter for the overall outcome. For more than three decades the common assumption amongst physicians was that of a low pH value, such as it is found on normal skin, is favorable for wound healing. However, investigations have shown that in fact, some healing processes such as the take-rate of skin grafts require an alkaline environment.
If pH adjustment is to be done, then the methods of delivery of that pH adjustment must be optimally brought together for maximum efficiency. Adjustment of wound pH using varying methods has been done for years using very slow, expensive, inaccessible means such as sugar mixtures and betadyne. Such hand-compounded methods are replete with opportunities for infection to occur, inconsistencies in batch production, and by no stability testing yielding unreliable shelf life data. In the past, anecdotal evidence led the wound care community down different paths in their search for optimum wound care and healing methods and compositions. It is also known that there is a key factor in hospital efficiency and better patient care for a Stage II wound not to be allowed to progress to a Stage III, resulting in that patient being able to be discharged from the facility. An added benefit of stopping a Stage II from becoming a Stage III wound is overall patient care cost reduction in the facility.
Dermatitis and other injury to the skin occurs when the skin is subjected to biological processes, environmental and lifestyle conditions, and/or conditions that breakdown the stratum corneum. The stratum corneum (SC), or outermost layer of the epidermis, consists of corneocytes embedded in lipid multilayers and serves as the main barrier for skin penetration of various topical drugs. The main purpose of this part of the skin is to reduce water loss, repel microbial infection, protect deeper layers, and provide a water-repellant layer. Damage to this layer can occur, for example, when an infant's skin is exposed for long periods to urine and feces, these waste products lower the skin pH and result in the breakdown of the stratum corneum, which is thinner in infants compared to adults. Although moisture alone will loosen this layer and allow for friction irritation to occur, urine breakdown by fecal enzymes can reduce, or acidify, the skin resulting in chemical irritation. Decubitus ulcers can occur when patients must spend long periods in bed, and the resulting pressure points on the skin cause irritation lesions, commonly called bedsores. Some studies have shown that 8-40% of intensive care patients suffer from decubitus ulcers. According to a 2004 study, the incidence rate for decubitus ulcers calculated 474,692 new cases per year, with 34,320 deaths resulting therefrom. Another study calculated that 8% of spinal cord patients died as a result of decubitus ulcers and their complications.
The anatomical localization of the main barrier against diffusional water loss through the skin has often been considered to be the horny layer. The relative importance of the different layers of the SC has long been discussed. Some consider the horny layer uniform in functional barrier characteristics, whereas others consider it nonidentical. Based on lipid analysis and barrier properties, it has been suggested that the lowest region of the horny layer is mainly responsible for preventing evaporative water loss. Previous studies have also shown that transepidermal water loss (TEWL) increases while SC pH value decreases with decreasing thickness of the horny layer. See, Assessment of Stratum Corneum Bartier Layer and pH Changes by Means of Tape Stripping, Tam Tiet, et al., JAAD, March 2005, incorporated by reference herein in its entirety.
The wound healing process, depending on the type of injury to the skin, is an intricate process that involves the steps of inflammation, proliferation, and remodeling. During inflammation, bacteria and debris are phagocytized and removed, and factors are released that cause the migration and division of cells involved in the proliferative phase.
The proliferative phase is characterized by angiogenesis, deposition of collagen, formation of granular tissue, re-epithelialization, and wound contraction. In angiogenesis, new blood vessels are formed by vascular endothelial cells. In fibroplasia and formation of granular tissue, fibroblasts grow and form a new, provisional extracellular matrix (ECM) by excreting collagen and fibronectin.
Simultaneously, re-epithelialization occurs, providing a new epithelial layer. It is at this stage that oxygenation of the skin is critical to wound healing.
In the remodeling phase, collagen is remodeled and realigned along tension lines and cells that are no longer needed are removed by apoptosis.
Animal studies have shown that several of the processes of skin healing and repair are affected by the subcutaneous partial pressure of oxygen (O2). For example, supplemental oxygen can lead to increased rate of collagen deposition, epithelialization and improved healing of split thickness grafts. Increased subcutaneous O2 has also been shown to improve bacterial defenses.
As is evident from the above descriptions, one of the important routes of administration of a drug for treating a skin or mucosal membrane is by topical application of a drug onto the skin or mucosal membrane. Such drugs can include antibiotics, antifungals, antivirals, anti-inflammatories, pH adjusters and analgesics.
Common treatments include use of zinc oxide pastes, powders, petroleum-based creams, and even mild steroid creams to reduce excess moisture, provide antibacterial activity or barriers, and to reduce damage caused by the body's own inflammatory processes. Similar treatments are used in hospital settings to treat adult patient decubitus ulcers.
Many products in the topical pharmaceutical market have been geared towards occlusive mixtures. These occlusive mixtures can be beneficial to distressed skin in that they tend to be effective in protecting skin from the elements, moisture, and other irritants such as excrement or secretions. Unfortunately, in the same way that occlusive topical compositions block skin access to harmful irritants, they simultaneously block skin access to oxygen and other agents that promote healing.
Occlusive topical compositions also tend to yield a thick, greasy consistency. These are often called barrier creams and ointments, and generally, they are petrolatum or zinc oxide based. Compositions of this nature can be difficult to spread thinly and evenly. Such compositions can also be difficult to clean without subjecting the underlying skin to friction that is likely to cause or worsen irritation or inflammation.
While describing the problems associated with occlusive compositions, U.S. Pat. No. 7,682,623 to Eini, discloses a pharmaceutical or cosmetic carrier or composition for topical application characterized by rheological properties which render the carrier or composition semi-solid at rest and a liquid upon application of shear forces thereto. The referenced patent relates that both pharmaceutical agents and ambient oxygen are impeded by an ointment or barrier with a petroleum (petrolatum) base. “The active drug ingredient, which is dissolved or dispersed in the petroleum carrier, is not efficiently absorbed into the wound tissue, thus the efficacy of the drug is affected.” Further, the patent states that “ . . . petroleum (petrolatum) restricts respiration of a wound tissue and is disturbing to the normal respiration of the skin.”
In addition, U.S. Pat. No. 6,013,271, to Doughty, et al., discloses a skin care composition in the form of an oil-in-water dispersion which comprises from about 1% to about 60% oil phase components. In detailing the benefits of water-based topical compositions over petroleum-based, the referenced patent states that a water-based composition “provides skin care cosmetic compositions which provide improvements in moisturizing, absorption, skin feel, skin care, and appearance characteristics and which in particular provide improved short and longer term moisturizing effectiveness, while at the same time reducing stickiness and avoiding a greasy feel on the skin. The compositions also display excellent stability characteristics at both normal and elevated temperatures.”
In addition, U.S. patent application Ser. No. 12/700,375 to Bartels, discloses methods and compositions for treating wounds, decubitus ulcers, diaper rash, burns, abrasions, and other irritations and relevant injuries, including, in one embodiment, the use of an aqueous or emollient medium having one or more pH raising ingredients in a composition specifically designed to deliver oxygen to the skin's surface.
The problem of the drawbacks, discomfort, and potential infection risk that occlusive mixtures pose would be addressed by the introduction of an acceptable nonocclusive composition and method of topical application. To address the issue in the field of over the counter topical medications, such nonocclusive composition must also comply with FDA labeling requirements for over the counter topical solutions.
Accordingly, there is still a need for nonocclusive topical compositions and methods of treatment for damaged or irritated skin that both protect the skin surface, assist in its barrier and water-retention functions while allowing the simultaneous delivery of therapeutic agents and oxygen to the skin in a convenient and efficient manner.